Uricosuric agent



United States Patent 3,337,407 URICOSURIC AGENT Clement A. Stone, Blue Bell, Pa., assignor to Merck & Co., Inc., Rahway, N.lI., a corporation of New Jersey No Drawing. Filed Feb. 24, 1965, Ser. No. 435,077 2 Claims. (Cl. 16765) This invention relates to uricosuric pharmaceutical preparations and particularly to medicinal formulations for the treatment of gout.

Gout is one manifestation of a high concentration of uric acid in the blood. A relatively high uric acid level results in the formulation of tophi in various portions of the body and if a tophus occurs in a joint the system of gout appear. The tophi frequently occur about the fingers and toes but other common sites are cartilage, epiphyseal portions of the bone, synovial membrane, bursae, ligaments and tendons. They vary in size from a pinpoint to a large marble. These tophi are collections of monosodiumurate crystals and they occur in persons having a high blood level of uric acid.

Uric acid is synthesized in the body and it also is an end product of food digestion in human metabolism. As it constantly is being formed it has to be either destroyed or excreted. About 50% of that formed in the body is excreted by the kidneys and the balance appears to be destroyed, most likely by the liver. The uric acid which is a metabolic product results from the hydrolysis in the gastro-intestinal tract of food nucleoproteins into the purine substances which are absorbed into the blood stream. These purines are principally adenine and guanine and by a process of oxidation in the tissues they are changed into uric acid.

The failure of the body to excrete sufficient uric acid or to destroy it results in an excessive amount of it in the blood stream, either as the free acid or as a sodium salt. When the uric acid concentration reaches a level above 6.0 mg./ 100 cc., sodium ura te crystals may be deposited into and about the joints and tendons. These resulting deposits may, in advanced cases, occur in many articular and periarticular sites.

The onset of gout is frequently at night with a metatarsophalangeal joint of one big toe the site of predilection. The pain is an intense burning one and the toe is extremely sensitive to jarring, vibration or touch. As the pain subsides, the joint becomes reddened and swollen with a feeling of increased local heat. Systemic reactions to acute gout include fever, headache, tachycardia, chills, malaise, anorexia, oliguria and leucocytosis. Full function of the affected joint may not return for two or three weeks and repeated attacks of gout may leave a permanently damaged joint.

As gout is a most painful and debilitating affliction it is important that therapeutic measures be available for its treatment. One of the common initial treatments of gout has been the administration of colchicine. Its administration to a sufferer results in relief of joint pain and subsidence of evidence of inflammation. Probenecid is used for both its propyhylactic and its therapeutic treatment of high serum uric acid levels. However, both of these medicinal agents have disadvantages in some instances as gasto-intestinal distress including anorexia and nausea may occur. In some instances, headaches, flushing, dizziness and anemia have been observed.

In accordance with the present invention the blood concentration of uric acid is reduced by administering to the patient the fi-isomer of 2chloro-10-(3-dimethylaminopropylidene)thioxanthene. For convenience, this is hereinafter referred to as B-isomer thioxanthene. It is disclosed in Examples 4 and 5 of Patent 3,046,283, which issued on July 24, 1962, in the name of Edward L. Engelhardt. The Example 4 points out that the free base is an oil and Example 5 states that the HCl salt melts at 205.5-206.5 C. The invention contemplates the use of the base as it may be administered in capsule form or in a liquid solution or suspension for oral consumption or for injection. The HCl or other salt form such as the maleate, etc., lends itself to tableting in the conventional manner, but it may be sold as a powder for measured use or be made up in the form of capsules, liquids, suppositories, in accordance with pharmaceutical practices.

The daily dose of the B-isomer thioxanthene, as its base, is within the range of 30 to 600 mg. and the most usual range will be between 40 and 200 mg. The total daily consumption should be administered in subdivided doses throughout the day so that an effective blood level is maintained at all times. It may be administered in one daily dose if it is prepared in known sustained release form.

Examples representative of the invention are the following.

EXAMPLE 1 A tablet containing 25 mg. of the p-isomer thioxanthene is made up by combining the following ingredients:

Kg. fi-isomer thioxanthene HCl 31.30 Silicate powder (Cab-O-Sil) 1.55 Lactose powder 13.00 Corn starch 7.75

These ingredients are mixed, comminuted and remixed and to it is added the following sieved ingredients:

Wood cellulose powder (Solka-Floc) 7.75 Calcium phosphate dibasic 86.70

This combination is mixed and to it is then added the following bolted ingredients:

Stearic acid powder, triple pressed 4.30 Magnesium stearate powder 1.75

This combination is mixed, then slugged, granulated, and

.to it is added:

Magnesium stearate powder 0.88

This granulation is then rolled and compressed into tablets weighing approximately 1.24 gm. each. The approximate yield is l,250,000 tablets.

One tablet is taken orally three or four times a day. This will generally favor a balance between production and excretion of uric acid, thereby retarding or eliminating the progress of the disease. Such administration will generally serve as a prophylactic treatment against gout.

In the event that the method of treatment of Example 1 does not sufiice or is considered to be excessive, resort may be made to Example 2.

EXAMPLE 2 A tablet containing 10 (or 50) mg. of the same drug is made up as in Example 1 and is taken orally three or four times daily. The doctor may use them to titrate the patient and select the dosage most suitable for the prophylactic or therapeutic treatment of the person. At the onset of an attack of gout, the higher dosages, evenup to 600 mg. daily, may be resorted to to diminish the severity of the afiliction, and in this ease up to twelve 50 mg. tablets would be taken daily.

EXAMPLE 3 An ampul containing 25 mg. per cc. of the same drug may be injected into a person suffering from an attack of gout to rapidly eliminate uric acid and diminish the attack. This may be repeated at frequent intervals so 3 that as much as 600 mg. daily is injected, to olfset the symptoms.

Administration by injection or as a suppository may be used as a prophylactic measure in persons not able to take the drug orally. The B-isomer thioxanthene has the distinct advantage that its side reactions are minimal. It has relatively low sedative and cardiovascular side effects and because of this less prominent central nervous system action, its uricosuric action i utilized to greater advantage.

What is claimed is:

1. The method of reducing the uric acid content of blood in humans which involves the daily administration pound: fl-isomer of 2-chl0ro-10-(3-dimethylaminopropylidene)-thioxanthene.

2. The method according to claim 1 in which the range is from 40 to 200 mg. daily.

References Cited UNITED STATES PATENTS 3,046,283 7/1962 Engelhardt 260-328 3,113,137 12/1963 Schaeren et a1. 260-328 3,116,291 12/1963 Petersen et al. 260328 ALBERT T. MEYERS, Primary Examiner.

JULIAN LEVITT, Examiner.

in subdivided doses of from 30 to 600 mg. of the com- 15 LEROY B. RANDALL, Assistant Examiner. 

1. THE METHOD OF REDUCING THE URIC ACID CONTENT OF BLOOD IN HUMANS WHICH INVOLVES THE DAILY ADMINISTRATION IN SUBDIVIDED DOSES OF FROM 30 TO 600 MG. OF THE COMPOUND: B-ISOMER OF 2-CHLORO-10-(3-DIMETHYLAMINOPROPYLIDENE)-THIOXANTHENE. 